El Ghouzzi Vincent, Csaba Zsolt, Olivier Paul, Lelouvier Benjamin, Schwendimann Leslie, Dournaud Pascal, Verney Catherine, Rustin Pierre, Gressens Pierre
Institut National de la Santé et de la Recherche Médicale, U676, Paris, France.
J Neuropathol Exp Neurol. 2007 Sep;66(9):838-47. doi: 10.1097/NEN.0b013e318148b822.
Apoptosis-inducing factor (AIF) deficiency compromises oxidative phosphorylation. Harlequin mice, in which AIF is downregulated, develop a severe mitochondrial complex I (CI) deficiency, suggesting that Harlequin mice may represent a natural model of the most common oxidative phosphorylation disorders. However, the brain phenotype specifically involves the cerebellum, whereas human CI deficiencies often manifest as complex multifocal neuropathologies. To evaluate whether this model can be used as to study CI-deficient disorders, the whole brain of Harlequin mice was investigated during the course of the disease. Neurodegeneration was not restricted to the cerebellum but progressively affected thalamic, striatal, and cortical regions as well. Strong astroglial and microglial activation with extensive vascular proliferation was observed by 4 months of age in thalamic, striatal, and cerebellar nuclei associated with somatosensory-motor pathways. At 2 months of age, degenerating mitochondria were observed in most cells in these structures, even in nondegenerating neurons, a finding that indicates mitochondrial injury is a cause rather than an effect of neuronal cell death. Thus, apoptosis-inducing factor deficiency induces early mitochondrial degeneration, followed by progressive multifocal neuropathology (a phenotype broader than previously described), and resembles some histopathologic features of devastating human neurodegenerative mitochondriopathies associated with CI deficiency.
凋亡诱导因子（AIF）缺乏会损害氧化磷酸化。在丑角小鼠中，AIF表达下调，会出现严重的线粒体复合体I（CI）缺乏，这表明丑角小鼠可能代表了最常见的氧化磷酸化障碍的一种天然模型。然而，其脑表型特别累及小脑，而人类CI缺乏通常表现为复杂的多灶性神经病理学改变。为了评估该模型是否可用于研究CI缺乏症，我们在疾病过程中对丑角小鼠的全脑进行了研究。神经退行性变并不局限于小脑，还逐渐影响丘脑、纹状体和皮质区域。在4月龄时，在与体感运动通路相关的丘脑、纹状体和小脑核中观察到强烈的星形胶质细胞和小胶质细胞激活以及广泛的血管增生。在2月龄时，在这些结构的大多数细胞中都观察到线粒体退化，甚至在未退化的神经元中也是如此，这一发现表明线粒体损伤是神经元细胞死亡的原因而非结果。因此，凋亡诱导因子缺乏会导致早期线粒体退化，随后出现进行性多灶性神经病理学改变（一种比先前描述更广泛的表型），并且类似于与CI缺乏相关的严重人类神经退行性线粒体病的一些组织病理学特征。
